Background: Osteoarthritis (OA) of the knee is a prevalent musculoskeletal disorder leading to pain and functional impairment. Conventional treatments often provide inadequate relief, necessitating exploration of alternative therapies. Objective: To evaluate the efficacy and safety of a single local injection of 0.5% bupivacaine in reducing pain and improving function in patients with painful knee OA. Methods: In this open-label, single-arm study, 40 patients aged 50 to 80 with symptomatic knee OA and moderate to severe pain (VAS > 5) despite standard treatments were enrolled. Each received a single intra-articular injection of 0.5% bupivacaine. Pain intensity (VAS) and functional outcomes (WOMAC) were assessed at baseline, 24 hours, 1 week, and 1 month post-injection. Adverse events were monitored throughout. Results: A statistically significant reduction in pain intensity was observed at 24 hours post-injection (VAS: 7.8 to 3.2; p < 0.001), with sustained relief up to 1 week. A mild increase in pain was noted by 1 month. WOMAC scores showed significant improvements in pain, stiffness, and physical function (p < 0.05). The injection was well-tolerated, with only minor transient swelling in a few cases. No serious adverse effects or systemic toxicity were recorded. Conclusion: A single injection of 0.5% bupivacaine provided significant short-term pain relief and functional improvement in patients with knee OA, with a favorable safety profile. These findings support its potential as an adjunctive therapy for acute exacerbations of knee OA pain. Further randomized controlled trials are warranted to compare its efficacy with other interventions and to assess long-term safety.